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- Title
Impact of regional 5-HT depletion on the cognitive enhancing effects of a typical 5-ht<sub>6</sub> receptor antagonist, Ro 04-6790, in the Novel Object Discrimination task.
- Authors
King, M.; Spicer, C.; Sleight, A.; Marsden, C.; Fone, K.
- Abstract
Selective 5-ht6 receptor antagonists like Ro 04-6790 prolong memory in many rodent preclinical paradigms, possibly by blocking tonic 5-HT-evoked GABA release and allowing disinhibition of cortico-limbic glutamatergic and cholinergic neurones. If this is the case, behavioural responses to Ro 04-6790 should be abolished by depletion of endogenous 5-HT, and selective lesions of dorsal raphé (DR) or median raphé (MR) 5-HT pathways would allow the neuroanatomical substrates underlying the cognitive effects of 5-ht6 receptor antagonists to be elucidated. This study compared the effect of Ro 04-6790 on novel object discrimination (NOD) before and after sham or 5,7-dihydroxytryptamine (5,7-DHT)-induced lesions produced by injection into the lateral ventricles (LV), DR or MR. NOD tests used a 4 h inter-trial interval (ITI) and Ro 04-6790 (10 mg kg−1 i.p.) was administered 20 min before the familiarisation trial. Brain region-specific 5-HT depletion was assessed by high performance liquid chromatography with electrochemical detection (HPLC-ED). Widespread LV or selective MR, but not DR lesions, abolished the ability of Ro 04-6790 to delay natural forgetting. Successful performance of all lesioned rats in subsequent ‘drug-free’ NOD tests using a 1 h ITI excluded the possibility of any confounding effects on visual acuity or motivation. The ability of Ro 04-6790 to prolong object recognition memory requires blockade of MR 5-HT function. Because DR lesions did not produce the expected depletion of striatal 5-HT an additional contribution of DR inputs to this region cannot be completely excluded.
- Publication
Psychopharmacology, 2009, Vol 202, Issue 1-3, p111
- ISSN
0033-3158
- Publication type
Academic Journal
- DOI
10.1007/s00213-008-1334-1